The 6-oxopurine phosphoribosyltransferases (PRTases) (EC:2.4.2.8 HG(X)PRT and/or XGPRT EC:2.4.22) are necessary for both survival and reproduction of many microorganisms (including protozoa and certain bacteria) because, unlike mammalian cells, such microorganisms are auxotrophic for the purine ring. Thus, these microorganisms depend on these enzymes for the synthesis of the 6-oxopurine nucleoside monophosphates required for RNA/DNA production. On the other hand, humans possess two metabolic pathways to synthesise nucleoside monophosphates: de novo and salvage. Partial inhibition of the human enzyme should not have any serious side-effects. This is based on the fact that humans with an inherited genetic defect which results in only 3% of normal activity of this enzyme lead normal lives.
Accordingly the 6-oxopurine PRTases represent a target with therapeutic potential. The reactions catalysed by these enzymes are shown in Scheme 1.

6-Oxopurine phosphoribosyltransferase is the generic name for enzymes which add a phosphoribosyl group from PRib-PP onto the N9 atom of a 6-oxopurine to form a nucleoside monophosphate. The 6-oxopurine PRTases found in nature vary in their specificities for the three naturally occurring 6-oxopurines, hypoxanthine, guanine and xanthine. The specific names given to 6-oxopurine PRTases denote this specificity. For example, the human enzyme is called hypoxanthine guanine PRTase (abbrev. HGPRT) because it can efficiently use both hypoxanthine and guanine as substrates. The Plasmodium falciparum enzyme is called HGXPRT because it can use xanthine in addition to hypoxanthine and guanine as substrates.
Some organisms (including human, other mammals and Plasmodium species) encode and synthesize only one 6-oxopurine PRTase. Other organisms encode and synthesize two 6-oxopurine PRTases. Of these enzymes, the best characterized are Escherichia coli XGPRT and HPRT (Guddat, L. W., S., Martin, J. L., Keough, D. T. and de Jersey, J. (2002) Crystal structures of free, IMP-, and GMP-bound Escherichia coli hypoxanthine phosphoribosyltransferase. Protein Sci. 11: 1626-1638). As the abbreviations indicate, the former enzyme prefers guanine and xanthine while the latter prefers hypoxanthine.
The 6-oxopurine PRTases are members of purine salvage pathways present in all or virtually all species. These pathways contain a variety of enzymes. Their function is to make all of the required purine nucleotides (for RNA and DNA synthesis and for other purposes) using preformed purines.
Many organisms (including humans and many microorganisms) can produce purine bases from simple precursor molecules by the pathway known as de novo synthesis. Organisms which lack the de novo pathway and depend absolutely on the activity of one 6-oxopurine PRTase for the synthesis of purine nucleotides and which are human or animal pathogens are therefore the prime targets for 6-oxopurine PRTase inhibitors. Such organisms include several protozoan parasites including the Plasmodium species responsible for human malaria and Helicobacter pylori the causative organisms of gastric ulcers. For bacterial strains, especially those resistant to current antibiotics, inhibitors of the 6-oxopurine PRTases are potential leads for the development of novel antibiotics. It is also proposed that combination therapy which includes the co-administration with inhibitors of the de novo pathway (such as azaserine) will be a successful therapy.
Acyclic nucleoside phosphonates (ANPs) are reverse transcriptase inhibitors and several ANP-based drugs are in current clinical use for the treatment of serious viral infections (e.g. Viread®, Vistide®, Hepsera®). These compounds consist of a nucleobase, either 6-aminopurine or pyrimidine, linked to a phosphonate group by an acyclic linker. 2-(Phosphonoethoxy)ethyl guanine (PEEG) and 2-(phosphonoethoxy)ethyl hypoxanthine (PEEHx) are good inhibitors of both human HGPRT and Plasmodium falciparum HGXPRT (PfHGXPRT):

PEEG and PEEHx have Ki values for human HGPRT of 1 μM and 3.6 μM respectively, and 0.1 μM and 0.3 μM for PfHGXPRT. ANPs are believed to be metabolically stable due to the presence of a phosphonate P—C linkage instead of a P—O phosphoester, making them resistant towards phosphomonoesterases and nucleotidases. ANPs are also believed to be stable because the bond between the purine and the linker is stable, in contrast to the bond between the purine and the ribose in purine nucleotides.
There are four major species of Plasmodium that infect humans and result in symptoms of malaria: falciparum, vivax. malariae and ovale. Plasmodium falciparum (pf) and Plasmodium vivax (Pv) are the most lethal and widespread with both species infecting around 500 million people per year, resulting in at least 1 million deaths per annum, mainly children. Drugs such as artemisinin and combination therapies, quinine, chloroquine, primaquine, are the only known treatments for malaria but, because of increasing resistance to these drugs as well as cost-effectiveness, there is an urgent need for the discovery of new targets and therapeutic leads for the development of potent anti-malarials. Likewise, there is an ongoing need for new agents that are effective against a range of other pathogenic microorganisms.